Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O=[Si]=O>CCO.[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CCO
Product: CC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 92.4 %

Procedure:
A mixture tert-butyl 4-[3-(acetylamino)phenyl]-1,2,3,6-tetra-hydro-1-pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH (10 mL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was passed through a pad of Celite 545 and the pad of Celite was washed with ethanol. The combined ethanol extracts were concentrated and chromatograghed, giving the desired product (660 mg). 1H NMR δ 7.80 (s, 1 H), 7.41-7.20 (m, 3 H), 6.94 (d, 1 H, J=7.5 Hz), 4.21 (m, 2 H), 2.75 (m, 2 H), 2.62 (m, 1 H), 2.16 (s, 3 H), 1.78 (m, 2 H), 1.56 (m, 2 H), 1.48 (s, 9 H).
Reaction SMILES: [C:1]([O:55]CC=C)(=[O:54])[CH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([O:16][C@:17]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53])([CH2:40][N:41]1[CH:45]=[N:44][CH:43]=[N:42]1)[C@H:18]([S:20][C@@H:21]1[CH2:26][O:25][C@@H:24](/[CH:27]=[CH:28]/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=2[F:39])[O:23][CH2:22]1)[CH3:19])=[O:15])=[O:5].O.C([SnH](CCCC)CCCC)CCC.CCCCCC>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([O:16][C@:17]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=1[F:53])([CH2:40][N:41]1[CH:45]=[N:44][CH:43]=[N:42]1)[C@H:18]([S:20][C@@H:21]1[CH2:26][O:25][C@@H:24](/[CH:27]=[CH:28]/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:32]=2[F:39])[O:23][CH2:22]1)[CH3:19])=[O:15])(=[O:5])[CH2:3][CH2:2][C:1]([OH:55])=[O:54]
Reactant: C=CCOC(=O)CCC(=O)OCc1ccccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)c1ccccc1COC(=O)CCC(=O)O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
Allyl 2-[[(1R,2R)-2-[[trans-2-[(1E,3E)-4-(4-cyano-2-fluorophenyl)-1,3-butadienyl]-1,3-dioxan-5-yl]thio]-1-(2,4-difluorophenyl)-1-[(1H-1,2,4-triazol-1-yl)methyl]propoxy]carbonyl]benzyl succinate (150 mg, 1.84×10-4 mol) obtained from Example 19-(2) and bis(triphenylphosphine)dichloropalladium (2 mg) were dissolved in dichloromethane (1.5 ml). To the mixture was added water (0.1 ml), and tributyltin hydride (80 mg, 2.7×10−4 mol) was slowly added thereto over a period of 5 minutes at room temperature. The resulting mixture was stirred at room temperature for 15 minutes further, and then hexane was added thereto. The liberated oily insoluble material was separated by removing the supernatant liquid slowly. The insoluble residue was further washed twice with hexane. The oily residue was subjected to chromatography on a silica gel (8 g) column (eluent; ethyl acetate), and then purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (123.9 mg, 87% yield) as a colorless amorphous solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[C:12]([CH3:20])([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH3:13])=[CH:7][CH:6]=1.[CH2:22]([S:26][CH2:27][C:28](=[CH2:32])[C:29](O)=[O:30])[CH2:23][CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C.C(OCC)(=O)C>CC(N(C)C)=O>[CH3:20][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:13])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:4][CH2:3][CH2:2][O:1][C:29](=[O:30])[C:28]([CH2:27][S:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH2:32])=[CH:6][CH:7]=1)=[O:21]
Reactant: C=C(CSCCCC)C(=O)O
Reactant: CC(C)(C(=O)c1ccc(SCCO)cc1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(CSCCCC)C(=O)OCCSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
1.0 g (3.2 mmol) of 1-[4-(2-Hydroxyethylthio)phenyl]-2-methyl-2-morpholin-4-yl-propane-1-one and 0.56 g (3.2 mmol) of 2-(butylthiomethyl)acrylic acid are dissolved in 20 ml of dry dimethylacetamide and cooled to −20° C. To the solution is added 0.68 g (3.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 5 ml of dry dimethylacetamide. The mixture is gradually warmed to room temperature and stirred overnight. To the mixture is added ethyl acetate. The mixture then is washed with saturated sodium chloride solution and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:2) as an eluent, and an oily product is obtained.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:11]([CH3:13])[CH:12]=1.C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1>[CH3:10][CH2:9][CH2:8][CH:7]([CH3:12])[CH3:6].[CH3:6][C:7]1[C:12]([B:22]([OH:23])[OH:21])=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(C)cc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC(C)C
Product: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 186.1 %

Procedure:
tert-Butyllithium (1.7 M solution in hexane, 36.2 ml, 61.6 mmol) is added dropwise to a solution of 3,5-dimethylbiphenyl (7.27 g, 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. under an atmosphere of nitrogen. The reaction mixture is stirred at −78° C. for 30 minutes, then trimethylborate (9.54 ml, 84 mmol) is added. The resulting mixture is stirred at −78° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture is acidified with 10% aqueous hydrochloric acid solution and extracted with diethyl ether (2×150 ml). The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give a yellow solid. Trituration with isohexane gives 3,5-dimethylbiphen-4-ylboronic acid as a white powder (5.89 g).
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[C:1]12([C:11]([O:13][CH:21]([C:27]([CH3:29])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(=O)C12CC3CC(CC(C3)C1)C2)C(C)=O
Temperature: 80 °C
Reaction time: 10 h

Procedure:
200 mmol of 1-adamantanecarboxylic acid are added to 100 mmol of sodium carbonate placed in 160 ml of DMF. The mixture is heated to 80° C. and then 200 mmol of ethyl 2-chloroacetoacetate in solution in 40 ml of DMF are added. The temperature and the stirring are maintained for three hours and then the mixture is left for 10 hours at room temperature. After evaporation of the DMF, the residue is taken up in 300 ml of water and 300 ml of ether. After extraction, drying and evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38]>C(Cl)Cl>[CH2:11]([C:4]1[S:3][C:2]2[NH:1][C:17](=[O:23])[N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccn1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(-c3ccccn3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 176.4 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-ethylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.32 g) and triethylamine (0.59 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added pyridin-2-amine (0.76 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (20 mL), sodium methoxide (28% methanol solution, 1.3 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.52 g, 70%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][CH:8]([SiH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[O:9][CH2:10][CH3:11])[CH3:6].CN(C)C1C=CC=CC=1.Cl.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:10]([O:9][CH:8]([SiH2:12][CH2:13][CH2:14][CH2:15][N:16]=[C:1]=[O:2])[O:7][CH2:5][CH3:6])[CH3:11]
Reactant: O=C(Cl)Cl
Reactant: CCOC(OCC)[SiH2]CCCN
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(OCC)[SiH2]CCCN=C=O
Reaction time: 3 h
Yield: 71.9 %

Procedure:
In 150 ml of toluene was dissolved 9.9 g of carbonyl chloride, and a solution of 19.1 g of γ-diethoxymethylsilylpropylamine and 24.2 g of N,N-dimethylaniline in 50 ml of toluene was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, N,N-dimethylaniline hydrochloride was removed by filtration, the filtrate was distilled to recover toluene, and a fraction having a boiling point of 91° C. to 93° C. under 9 mmHg was collected. Then, 1 g of sodium benzoate was added to the fraction. The mixture was then stirred for 3 hours and the pH value became 7. Excessive sodium benzoate and the precipitate were removed by filtration, and the filtrate was distilled to obtain 15.6 g of γ-diethoxymethylsilylpropyl isocyanate as a fraction having a boiling point of 80° C. to 82° C. under 5 mmHg. The product remained stable, even when stored for more than 6 months.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36](Br)([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH:36]([CH3:38])[CH3:37])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CC(C)Br
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: COc1ccc(CC2c3c(OC(C)C)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with isopropyl bromide
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].CN(C)C=O>CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(C)(C)C)cc1OS(=O)(=O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)C)cc1C#C[Si](C)(C)C
Yield: 69.6 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 5-tert-butyl-2-methyl-phenyl ester (Intermediate 108, 0.28 g, 0.94 mmol), triethyl amine (3 mL), trimethylsilyl acetylene (1 mL, 7 mmol), N,N-dimethylformamide (6 mL) and dichlorobis(triphenylphosphine)palladium(11) (0.053 g, 0.076 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using hexane as the eluent, the title compound (0.16 g, 69%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].O.C(OCC)(=O)C>[CH3:9][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:14]/[C:2]2[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C=Cc1cccc(C)c1
Reactant: Nc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cccc(/C=C/c2cccc(N)c2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-bromoaniline (545 uL), 3-methylstyrene (780 uL), tri(o-tolyl)phosphine (60 mg), Pd(OAc)2 (10 rag), and triethylamine (2.5 mL) was prepared in a sealed tube under argon atmosphere. The reaction was heated at 100° C. for 4 h, then cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed with water and dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (20:1-5:1 hexane/EtOAc) provided the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A suspension of 4-bromo-1H-pyrazole (10 g) in tetrahydrofuran (230 ml) was stirred for 1 hr at room temperature. While argon gas was provided, sodium hydride was slowly added at 0° C. to the suspension, followed by stirring for 30 min and then for an additional 30 min at room temperature. Then, trityl chloride (22.8 g) was slowly added at 0° C. to the suspension with stirring for 20 min. Further stirring was conducted for 3 hrs at room temperature before the reaction was terminated. Following the removal of excess sodium hydride with distilled water (3 ml) from the reaction at 0° C., the tetrahydrofuran solvent was evaporated in a vacuum and the concentrate thus obtained was diluted in ethyl acetate (200 ml) and washed with distilled water (200 ml) and then with brine (200 ml). The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation in vacuo. The residue was diluted in methylene chloride (2 ml) and recrystallized in methanol (200 ml) to give 4-bromo-1-trityl-1H-pyrazole (25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCCCCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 14 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and azepane according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 14%; MS: m/z=413 (M+H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Br[C:35]1[N:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:41][C:38]1[CH:37]=[N:36][C:35]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:4][CH2:3][C:2]([F:1])([F:32])[F:33])=[C:7]([CH3:21])[CH:8]=2)=[N:40][CH:39]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: Clc1cnc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ncc(Cl)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A reaction mixture of 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoic acid (0.500 g), 2-bromo-5-chloropyrimidine (0.251 g), tetrakistriphenylphosphinepalladium (0.125 g), sodium carbonate (0.343 g), DME (3 mL) and water (1 mL) was stirred at 130° C. for 1 hr under microwave irradiation under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.407 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][C:25]1[C:30](=[O:31])[C:29]([CH3:32])=[C:28]([CH3:33])[C:27](=[O:34])[C:26]=1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=1)[C:41](O)=[O:42]>O.C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:26]3[C:27](=[O:34])[C:28]([CH3:33])=[C:29]([CH3:32])[C:30](=[O:31])[C:25]=3[CH3:24])[CH:37]=[CH:38][C:39]=2[OH:45])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1=C(C)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccncc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 6.7 %

Procedure:
4-Aminopyridine (0.103 g, 1.096 mmol), triethylamine (0.111 g, 1.096 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.185 g, 1.096 mmol) were added to a methylene chloride solution (100 ml) of 5-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.730 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) to obtain the titled compound (0.020 g, 0.049 mmol, 7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:18])=[CH:5][CH:4]=1.CO[C:21]1(OC)[CH2:25][CH2:24][CH2:23][N:22]1[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[C:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:26])[C:10]2=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1
Reactant: COC1(OC)CCCN1C
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1

Procedure:
1-(4-Methoxyphenyl)-2(1H,3H)-indolone (49 g, 0.205 mole), N-methyl-2-pyrrolidone dimethyl acetal (ca. 80%, 53 g, 0.245 mole, Ber, 97, pp. 3081-7, 1964) and 1000 ml chloroform were refluxed under nitrogen for 1.5 hours. The reaction mixture was cooled and evaporated in vacuo to solids. Two recrystallizations from ethyl acetate gave purified title product, 44.7 g, m.p. 90°-93° C. Thirty grams of this material were dried at 80° C./15 mm Hg for 20 hours to give 26.1 g of title product, m.p. 127°-9° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:27]([NH:34][CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:6]([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([N:34]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:35])=[O:17])(=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: CN(Cc1ccccc1)C(=O)[C@@H]1CC(=CCl)CN1C(=O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and N-benzyl-N-methylamine the title compound was obtained in 62% purity by LC/MS. MS(ESI+): m/z=369.4.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4].C(O)=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:17])([F:18])[C:3]([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: O=C1CC[C@H](NC(=O)C(F)(F)F)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Temperature: 50 °C
Reaction time: 22 h
Yield: 72.9 %

Procedure:
A solution of Intermediate 1b (161 g, 624 mmol) in DMF (2 L) was vacuum degassed with argon. [N-[(1R,2R)-2-(Amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium (CAS: 192139-92-7, 9.95 g, 15.6 mmol) was then added. Formic acid (57.5 g, 1.25 mol) was added slowly to ice cold triethylamine (126 g, 1.25 mol) with stirring, this was then added to the DMF solution. The resulting reaction mixture was heated to 50° C. (internal temperature) for 41 h with stirring. LCMS analysis of the reaction indicated it was incomplete, therefore a solution of formic acid (14.4 g, 313 mmol) was added slowly to ice cold triethylamine (31.6 g, 312 mmol), this was then added to the reaction mixture. Heating was continued for an additional 22 h. After cooling, the mixture was concentrated in vacuo to give an orange residue. The residue was diluted with ethyl acetate (1.5 L) and the solution washed with brine (2×0.5 L). The organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Silica, 3 Kg, 0-50% ethyl acetate in cyclohexane) gave Intermediate 1c (118 g, 73%). 97.5 d.e.% determination by LCMS Rt 3.37 min, M-H 258 (93.7%, desired); Rt 3.25 min, M-H 258 (1.2%, trans isomer). 1H NMR (400 MHz, CDCl3): 1.88-1.92 (1H, d, J=4.8 Hz), 1.98-2.18 (4H, m), 4.80-4.88 (1H, m), 5.165-5.24 (1H, m), 6.70-6.80 (1H, br s), 7.25-7.30 (1H, m), 7.30-7.40 (2H, m), 7.45-7.50 (1H, m).